Method of preparing 1-amino-2, 6-dimethylpiperidine

ABSTRACT

The present invention relates to improved processes for the preparation of 1-amino-2,6-dimethylpiperidine whereby the yield is more than 90%. The processes involve the hydrogenation of 1-nitroso-2,6-dimethylpiperidine in the presence of a palladium catalyst partly poisoned with iron ions but in the substantial absence of water or other solubilizing agents added to the reaction vessel.

The invention relates to a process for the preparation of1-amino-2,6-dimethylpiperidine.

1-Amino-cis-2,6-dimethylpiperidine is a key intermediate product in thesynthesis of the loop saluretic clopamide(4-chloro-N-(cis-2,6-dimethylpiperidino-sulfamoylbenzamide) and thecardiovascular agent pirsidomine(3-(cis-2,6-dimethylpiperidino)-N-(4-methoxybenzoyl)-sydnonimine).

All the known preparation processes for 1-amino-2,6-dimethylpiperidineare based on reduction of 1-nitro-so-2,6-dimethylpiperidine. All show anincomplete conversion and above all ecological deficiencies.

Furthermore, the production of large amounts of waste salts in thereduction with sodium dithionite (C.G. Overberger, J.G. Lombardino andR.G. Hiskey, J. Org. Chem. 22 (1957) 858) is a disadvantage.

The use of zinc in dilute acetic acid as the reducing agent (E. Juckerand A. Lindamann, Helv. Chim. Acta, 45 (1962) 2316-2325, in particular2323) leads to a considerable heavy metal pollution of the resultingwaste water.

Reduction with complex hydrides, such as lithium aluminum hydride inether (C.G. Overberger, L.C. Palmer, S.S. Marks and N.R. Byrd, J. Am.Cham. Soc. 77 (1955) 4100) or bis(2-methoxyethoxy)-sodium aluminumhydride in toluene (M. Londyn and M. Borovicka, Czechoslovakian Patent253243, applied for on 21.01.1986) cannot be carried out on a largerscale for safety reasons. A process is known from U.S. Pat. No.2,979,505 for the preparation of substituted hydrazines, such as, forexample, N-aminopiperidine, in which the corresponding nitrosamines arehydrogenated in the presence of a palladium catalyst which contains acertain amount of a soluble iron salt. The hydrogenation of heterocyclicnitrosamines, such as, for example, of nitrosopiperidine, by thisprocess is carried out in aqueous or ethanolic solution.

According to Hungarian Patent 15614, the preparation of1-amino-cis-2,6-dimethylpiperidine by this process is unsatisfactoryboth in respect of the yield (65%) and in respect of the selectivity (60to 70%). According to the process of Hungarian Patent 15614,1-amino-cis-2,6-dimethylpiperidine is therefore prepared by nitrosationof cis-2,6-dimethylpiperidine and hydrogenation of the resulting nitrosocompound in aqueous ammoniacal solution in the presence of a palladiumcatalyst partly poisoned with an Fe(II) salt, the two reactions beingcarried out in the absence of chloride ions. This process showsconsiderable problems both in the reaction and in the working-up of thereaction mixture obtained. Thus, for example, the use of ammoniarequires additional process technology measures to avoid corrosion andemission. Furthermore, the amount of ammonia used is high (100 to 150 gof ammonia per kg of product). The incomplete conversion, which causesthe product to contain still unreacted 1-nitroso-2,6-dimethylpiperidine,is, as in the other processes, a disadvantage. In the process ofHungarian Patent 15614, it is still at least 3%. Nevertheless, the maindifficulty is the large amount of water in the reaction mixture, whichis caused by the process and makes isolation of the product very muchmore difficult.

During subsequent rectification, the product and by-product(cis-2,6-dimethylpiperidine) pass over together with water (as a rule at85° to 95° C./atmospheric pressure), so that there is the prospect ofisolation of the product only if extremely expensive columns areemployed. Only multi-stage extractor processes remain as alternativesfor isolation of the product. The organic solvents used here requireincreased safety measures and treatment of the waste water and wasteair. To remove the relatively strongly basic by-product2,6-dimethylpiperidine the addition of a corresponding amount of acidsubstances is necessary, which means that the waste water is pollutedeven more (M. Londyn, Czechoslovakian Patent 253898).

The object of the present invention was therefore to provide a processfor the preparation of 1-amino-2,6-dimethylpiperidine by reduction of1-nitroso-2,6-dimethylpiperidine which does not have the disadvantagesof the processes which have been disclosed to date and by which, inparticular, a complete conversion is achieved.

The invention thus relates to a process for the preparation of1-amino-2,6-dimethylpiperidine by catalytic hydrogenation of1-nitroso-2,6-dimethylpiperidine using a palladium catalyst partlypoisoned with iron ions. The process according to the invention ischaracterized in that it is carried out without initial introduction ofa solvent and a solubilizing agent into the reaction vessel.

In carrying out the process according to the invention, only thepalladium catalyst partly poisoned with iron ions and the startingsubstance 1-nitroso-2,6-dimethylpiperidine are employed in thehydrogenation.

The palladium catalyst is preferably employed in an amount such that theamount of Pd is 0.1 to 10 mol%, based on the1-nitroso-2,6-dimethylpiperidine.

The palladium catalysts used are, in particular, those in which thepalladium is adsorbed onto a support, preferably charcoal or aluminumoxide, and which have a Pd content of 1 to 10% by weight.

The catalyst is partly poisoned by addition of a soluble iron saltbefore the reaction. Fe(II) sulfate is particularly suitable as thesoluble iron salt here. The molar ratio of Pd:Fe is preferably (20 to0.5):1. The partial poisoning of the palladium catalyst can be carriedout, for example, by stirring the catalyst and the iron salt in water,expediently under an inert gas, for about 10 to 120 minutes. The partlypoisoned palladium catalyst is then separated off, for example filteredoff with suction or filtered off, and if appropriate dried by suction orother means. However, it can also be employed in the moist form.

The hydrogenation is carried out at normal temperature or preferably atelevated temperature, for example at 20° to 80° C., and, for example,under a hydrogen pressure of 1 to 100 bar. A reaction temperature of 30°to 50° C. and/or a hydrogen pressure of 2 to 25 bar is particularlypreferred here.

Surprisingly, a practically complete conversion of more than 99% isachieved by the process according to the invention. The startingsubstance 1-nitroso-2,6-dimethylpiperidine used is detectable in thereaction product, if at all, only in traces using sensitive detectionmethods.

The reaction mixture which remains in the process according to theinvention after the catalyst has been filtered off can be worked up, forexample, by rectification. The rectification can be carried out in therange from 20 mbar to atmospheric pressure. Vacua in the range from 50to 300 mbar are preferred here. The top product comprises2,6-dimethylpiperidine and water. This mixture can be re-used in thepreparation of 1-nitroso-2,6-dimethylpiperidine. The bottom productwhich remains comprises 1-amino-2-6-dimethylpiperidine to the extent ofmore than 99% and can be passed in this form to the synthesis of themedicaments mentioned at the outset. The boiling points of the topproduct and bottom product are 40 to 50 degrees apart, so that a simplecolumn is adequate for isolation of the products.

If the remaining traces of impurities (for example1-nitroso-2,6-dimethylpiperidine) are likewise to be removed from theproduct, this can be effected by further rectification, the1-amino-2,6-dimethylpiperidine being collected as the second fraction.

The process according to the invention is equally suitable for thepreparation of 1-amino-cis-2,6- or -trans-2,6-dimethylpiperidine.

Compared with the known preparation processes, the process according tothe invention offers several considerable advantages. Thus, for example,isolation of the products is drastically simplified. In the reaction,the 1-nitroso-2,6-dimethylpiperidine employed is reacted to the extentof more than 99%, that is to say practically completely, with asimultaneously high selectivity of more than 90%, it being possible forthe selectivity to be increased further by recycling the by-product. Thevolume yield is high (up to, for example, 500 g/l of autoclave volume).Since only small amounts of water are required for the pretreatment ofthe catalyst and the cleaning of the apparatus, a drastic reduction inthe amount of waste water is achieved by the process according to theinvention. Organic solvents and solubilizing agents, such as ammonia,are avoided completely. Additional process technology measures arethereby also eliminated completely, and safety is improved. Because ofthe few process steps, a high space/time yield and a significant savingin energy also result.

EXAMPLE

20 g of a Pd catalyst absorbed onto A charcoal and having a Pd contentof 10% by weight and 5 g of FeSO₄ ×7 H₂ O are stirred in 100 ml ofdistilled water under a nitrogen atmosphere for 1 hour. The catalyst isthen filtered off over a filter paper and sucked dry. The adheringmoisture makes up about 50% by weight.

A 11 autoclave is charged with this catalyst paste and 284 g of1-nitroso-cis-2,6-dimethylpiperidine. At 40° C. and under a hydrogenpressure of 6 bar, the hydrogenation is finished after 12 hours.

After the catalyst has been filtered off, the reaction mixture containsmore than 90% of 1-amino-cis-2,6-dimethylpiperidine, 9% by weight ofcis-2,6-dimethylpiperidine and 1-nitroso-cis-2,6-dimethylpiperidine intraces which are only detectable by gas chromatography (conversion >99%;selectivity=90% ). 50 to 60 ml of water are also obtained in thishydrogenation. This is composed of the residual moisture of the catalystand the water of reaction formed. (The concentrations of product andby-product can be determined side by side by titration with dilutehydrochloric acid, but preferably by means of gas chromatography.)

The reaction is followed by rectification over a Kerapack column under100 mbar. The by-product cis-2,6-dimethylpiperidine passes over togetherwith the water at 39° to 43° C. and the product1-amino-cis-2,6-dimethylpiperidine passes over at 90° to 96° C.

We claim:
 1. In the process for the preparation of1-amino-2,6-dimethylpiperidine by catalytic hydrogenation of1-nitroso-2,6-dimentylpiperidine in the presence of a palladium catalystpartly poisoned with iron ions, the improvement which comprisesincreasing the yield to more than 90% by adding to a reaction vessel areaction mixture consisting essentially of the1-nitroso-2,6-dimethylpiperidine, said palladium catalyst and hydrogengas, in the substantial absence of water or other solubilizing agents,and subjecting the reaction mixture to hydrogenation conditions toproduce 1-amino-2,6-dimethylpiperidine in a yield of more than 90%. 2.Process according to claim 1, characterized in that the palladiumcatalyst is used in an amount such that the amount of Pd is 0.1 to 10mol %, based on the 1-nitroso-2,6-dimethylpiperidine.
 3. Processaccording to claim 1, characterized in that a Pd-supported catalyst,having a Pd content of 1 to 10% by weight is employed.
 4. Processaccording to claim 1, in which the ratio of Pd:Fe is (20 to 0.5):1. 5.Process according to claim 1, in which1-nitroso-cis-2,6-dimethylpiperidine is employed as the startingreactant.
 6. Process according to claim 1, in which the hydrogenation iscarried out at a temperature of 20° to 80° C.
 7. Process according toclaim 1, in which the hydrogenation is carried out under a hydrogenpressure of 1 to 100 bar.
 8. Process according to claims 1, in whichwhen the hydrogenation reaction is completed, the catalyst is separatedoff and the reaction is rectified.
 9. Process according to claim 8,characterized in that the reaction is separated into aqueous2,6-dimethylpiperidine and 1-amino-2,6-dimethylpiperidine during therectification.
 10. Process according to claim 9, characterized in thatthe aqueous 2,6-dimethylpiperidine which has been separated off isre-used to produce 1-nitrosa-2,6-dimethylpiperdine.
 11. Processaccording to claim 6 in which the temperature is between 30° and 50° C.12. Process according to claim 7 in which the hydrogen pressure isbetween 2 and 25 bar.
 13. Process according to claim 3 in which thesupported catalyst is a Pd/C catalyst.
 14. Process according to claim 3in which the supported catalyst is a Pd/Al₂ O₃ catalyst.